Metabolic Orchestration of Cell Death by AMPK-mediated Phosphorylation of RIPK1

Overview

Journal Science

Specialty Science

Date 2023 Jun 29

PMID 37384704

Authors

Tao Zhang

Daichao Xu

Elijah Trefts

Mingming Lv

Hiroyuki Inuzuka

Guobin Song

Min Liu

Jianlin Lu

Jianping Liu

Chen Chu

Min Wang

Huibing Wang

Huyan Meng

Hui Liu

Yuan Zhuang

Xingxing Xie

Fabin Dang

Dongxian Guan

Yuqin Men

Shuwen Jiang

Cong Jiang

Xiaoming Dai

Jing Liu

Zhen Wang

Peiqiang Yan

Jingchao Wang

Zhenbo Tu

Mrigya Babuta

Emily Erickson

Alissandra L Hillis

Christian C Dibble

John M Asara

Gyongy Szabo

Piotr Sicinski

Ji Miao

Yu-Ru Lee

Lifeng Pan

Reuben J Shaw

Junying Yuan

Wenyi Wei

Affiliations

Soon will be listed here.

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid -deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.

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